The present invention relates to processes for the synthesis of steroidal glycosides, and particularly to the preparation of steroidal peracyl glycosides used as intermediates therein.
Tigogenin beta-O-cellobioside is a known compound having utility in the treatment of hypercholesterolemia and atherosclerosis (Malinow, U.S. Pat. Nos. 4,602,003 and 4,602,005; Malinow et al., Steroids, vol. 48, pp. 197-211, 1986). Each patent discloses a different synthesis of this compound from alpha-D-cellobiose octaacetate; the first via the glycosyl bromide heptaacetate which is coupled with tigogenin in the presence of silver carbonate, and finally hydrolyzed; and the second via direct stannic chloride catalyzed coupling of the cellobiose octaacetate with tigogenin in methylene chloride, again followed by hydrolysis. In Malinow et al., reaction of cellobiose octaacetate with titanium tetrabromide gave the cellobiosyl bromide heptaacetate, which was coupled with tigogenin by means of mercuric cyanide, and then hydrolyzed. All of these methods have serious drawbacks for producing bulk material to be used as a pharmaceutical drug. A desirable goal, met by the present invention, has been to devise synthetic methods which avoid toxic and/or expensive reagents, and which cleanly produce the desired tigogenin beta-O-cellobioside, avoiding tedious and expensive purification steps.
Schmidt, Angew. Chem. Int. Ed. Engl., vol. 25, pp. 212-235 (1986) has reviewed the synthesis and reactions of O-glycosyl trichloroacetimidates formed by the reaction of sugars possessing a 1-hydroxy group (but with other hydroxy groups protected, e.g., by benzyl or acetyl) with trichloroacetonitrile in the presence of a base. There is preferential formation of the alpha-anomer when sodium hydride is used as base, and preferential formation of the beta-anomer when the base is potassium carbonate. The alpha anomer of tetrabenzylglucosyl trichloroacetimidate when coupled with cholesterol gave anomeric mixtures which varied with catalyst (p-toluenesulfonic acid or boron trifluoride etherate) and temperature (-40.degree. to +20.degree. C.). On the other hand, both the alpha and beta anomers of tetraacetylglucosyl analog reportedly yielded exclusively beta-anomeric products.
Thus, there has been a continuing search in this field of art for improved methods of stereocontrolled syntheses of steroidal glycosides. For example, Gilbert Stork, J. Am. Chem. Soc. 1992, 114, 1087 and the authors cited therein support the need for better stereoselective glycoside syntheses.